Hostname: page-component-cd9895bd7-hc48f Total loading time: 0 Render date: 2024-12-24T17:14:57.451Z Has data issue: false hasContentIssue false
  • English
  • Français

Serum Brain-Derived Neurotrophic Factor Mediates the Relationship between Abdominal Adiposity and Executive Function in Middle Age

Published online by Cambridge University Press:  30 March 2016

Sonya Kaur ,
Mitzi M. Gonzales ,
Takashi Tarumi ,
Astrid Villalpando ,
Mohammed Alkatan ,
Martha Pyron ,
Hirofumi Tanaka  and
Andreana P. Haley
Sonya Kaur
Affiliation:
Department of Psychology, Austin, Texas
Mitzi M. Gonzales
Affiliation:
Department of Psychology, Austin, Texas
Takashi Tarumi
Affiliation:
Department of Kinesiology and Health Education, Austin, Texas
Astrid Villalpando
Affiliation:
Department of Psychology, Austin, Texas
Mohammed Alkatan
Affiliation:
Department of Kinesiology and Health Education, Austin, Texas
Martha Pyron
Affiliation:
Department of Kinesiology and Health Education, Austin, Texas Medicine in Motion, Austin, Texas
Hirofumi Tanaka
Affiliation:
Department of Kinesiology and Health Education, Austin, Texas
Andreana P. Haley*
Affiliation:
Department of Psychology, Austin, Texas Imaging Research Center, The University of Texas at Austin, Austin, Texas
*
Correspondence and reprint requests to: Andreana P. Haley, Department of Psychology, The University of Texas at Austin, 108 East Dean Keeton, Stop A8000, Austin, TX 78712. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Objectives: Excessive adipose tissue, especially in the abdominal area, is associated with increased risk of dementia in older adults. However, the mechanisms underlying this relationship are poorly understood. As increased adiposity is also associated with lower circulating levels of brain-derived neurotrophic factor (BDNF), a key molecule modulating brain plasticity and neuronal regeneration, we hypothesized that the changes in cognition that occur as a result of excessive abdominal adiposity would be driven by lower levels of circulating BDNF. Methods: Fasting blood samples were obtained from 60 participants aged 40–60 years (mean±SD=52.3±5.6) and BDNF levels were assessed with an enzyme linked immunosorbent assay. Abdominal adiposity was measured using a ratio of waist circumference to hip circumference (WHR). Participants also completed a neuropsychological assessment battery to assess executive function. Statistical mediation was assessed using traditional causal steps and nonparametric bootstrapping. Results: Higher WHR was significantly associated with poorer performance on the Controlled Oral Word Association (COWA) letter fluency test (β=−0.489; p=.003) and lower levels of circulating BDNF (β=−0.345; p=.006). Linear regression and bootstrapping methods indicated that BDNF fully mediated the relationship between WHR and performance on the COWA (β=0.60; 95% confidence interval [−3.79, −0.26]). Conclusions: The relationship between higher WHR and verbal fluency was fully statistically mediated by circulating BDNF levels. The BDNF pathway is thus a useful probable mechanism through which executive function decline occurs in individuals with high abdominal adiposity. BDNF enhancing interventions (physical exercise and dietary restriction) could thus be used to improve executive function in these individuals. (JINS, 2016, 22, 1–8)

Keywords

Central obesityCognitive declineCardiorespiratory fitnessExecutive functionVisceral fatBrain derived neurotrophic factor
Type
Research Articles
Information
Journal of the International Neuropsychological Society , Volume 22 , Issue 5 , May 2016 , pp. 493 - 500
Copyright
Copyright © The International Neuropsychological Society 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Alberti, K., Eckel, R.H., Grundy, S.M., Zimmet, P.Z., Cleeman, J.I., Donato, K.A., & Smith, S.C. Jr. (2009). Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation, 120, 1640–1645.CrossRefGoogle Scholar
Aschbacher, K., O’Donovan, A., Wolkowitz, O.M., Dhabhar, F.S., Su, Y., & Epel, E. (2013). Good stress, bad stress and oxidative stress: Insights from anticipatory cortisol reactivity. Psychoneuroendocrinology, 38, 1698–1708.CrossRefGoogle ScholarPubMed
Baron, R.M., & Kenny, D. (1986). The moderator mediator variable distinction in social psychological research: Conceptual, strategic and statistical considerations. Journal of Personality and Social Psychology, 51, 1173–1182.CrossRefGoogle ScholarPubMed
Bekinschtein, P., Cammarota, M., Katche, C., Slipczuk, L., Rossato, J.I., Goldin, A., & Medina, J.H. (2007). BDNF is essential to promote persistence of long term memory storage. Proceedings of the National Academy of Sciences of the United States of America, 7, 2711–2716.Google Scholar
Bekinschtein, P., Cammarota, M., Igaz, L.M., Bevilaqua, L.R.M., Izquierdo, I., & Medina, J.H. (2007). Persistence of long-term memory storage requires a late protein synthesis and BDNF-dependent phase in the hippocampus. Neuron, 53, 261–277.CrossRefGoogle ScholarPubMed
Borg, G.A. (1982). Psychophysical bases of perceived exertion. Medicine and Science in Sports and Exercise, 14, 377–381.CrossRefGoogle ScholarPubMed
Brady, C.B., Spiro, A., McGlinchey-Berroth, R., Milberg, W., & Gaziano, J.M. (2001). Stroke risk predicts verbal fluency decline in healthy older men: Evidence from the Normative Aging Study. The Journal of Gerontology Series B: Psychological Science Social Science, 56, 340–346.CrossRefGoogle ScholarPubMed
Cereda, E., Sansone, V., Meola, G., & Malavazos, A.E. (2007). Increased visceral adipose tissue rather than BMI as a risk factor for dementia. Age Ageing, 36(5), 488–491. doi:10.1093/ageing/afm096 CrossRefGoogle ScholarPubMed
Chen, Z.Y., Patel, P., Sant, D., Meng, C.X., Teng, K.K., Hempstead, B.L., & Lee, F.S. (2004). Variant brain derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity dependent secretion of wild type BDNF in neurosecretory cells and cortical neurons. Journal of Neuroscience, 24, 4401–4411.CrossRefGoogle ScholarPubMed
Cheng, A., Wang, S., Cai, J., Rao, M.S., & Mattson, M.P. (2003). Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Developmental Biology, 258, 319–333.CrossRefGoogle Scholar
Cserjesi, R., Molnar, D., Luminet, O., & Lenard, L. (2007). Is there any relationship between obesity and mental flexibility in children? Appetite, 49, 675–678.CrossRefGoogle ScholarPubMed
Doyle, P., Cusin, I., Rohner-Jeanrenaud, F., & Jeanrenaud, B. (1995). Four day hyperinsulinemia in euglycemic conditions alters local cerebral glucose utilization in specific brain nuclei of freely moving rats. Brain Research, 684, 47–55.CrossRefGoogle ScholarPubMed
Duan, W., Lee, J., Guo, Z., & Mattson, M.P. (2001). Dietary restriction stimulated BDNF production in the brain and thereby protects neurons against excitotoxic injury. Journal of Molecular Neuroscience, 16, 1–12.CrossRefGoogle ScholarPubMed
Elias, M., Elias, P., Sullivan, L., Wolf, P., & D’Agostino, R. (2003). Lower cognitive function in the presence of obesity and hypertension: The Framingham heart study. International Journal of Obesity, 27, 260–268.CrossRefGoogle ScholarPubMed
Erickson, K., Voss, M.W., Prakash, R.S., Basak, C., Szabo, A., Chaddock, L., & Kramer, A.F. (2011). Exercise training increases size of the hippocampus and improves memory. Proceedings of the National Academy of Sciences of the United States of America, 108, 3017–3022.CrossRefGoogle ScholarPubMed
Escobar, M.L., Figuera-Guzman, Y., & Gomez-Palacio-Schjetnan, A. (2003). In vivo insular cortex LTP induced by brain-derived neurotrophic factor. Brain Research, 991, 274–279.CrossRefGoogle ScholarPubMed
Estevez, A.G., Spear, N., Manuel, S.M., Radi, R., Henderson, C.E., … Beckman, J.S. (1998). Nitric oxide and superoxied contribute to motor neuron apoptosis induced by trophic factor deprivation. The Journal of Neuroscience, 18, 923–931.CrossRefGoogle ScholarPubMed
Gall, C., & Lauterborn, J. (1992). The dentate gyrus as a model system for studies of neurotrophin regulation. Epilepsy Research, 7, 171–185.Google Scholar
Gonzales, M., Tarumi, T., Miles, S., Tanaka, H., Shah, F., & Haley, A. (2010). Insulin sensitivity as a mediator of the relationship between body mass index and working memory related brain activation. Obesity (Silver Spring), 18, 2131–2137.CrossRefGoogle ScholarPubMed
Gonzales, M.M., Tarumi, T., Kaur, S., Nualnim, N., Fallow, B.A., Pyron, M., & Haley, A.P. (2013). Aerobic fitness and the brain: Increased N-acetyl-aspartate and choline concentrations in endurance-trained middle aged adults. Brain Topography, 26, 126–134.CrossRefGoogle ScholarPubMed
Gustafson, D., Lissner, L., Bengtsson, C., Bjorkelun, C., & Skoog, I. (2004). A 24-year follow up of body mass index and cerebral atrophy. Neurology, 63, 1876–1881.CrossRefGoogle ScholarPubMed
Gustafson, D., Rothenberg, E., Blennow, K., Steen, B., & Skoog, I. (2003). An 18-year follow up of overweight and risk of Alzheimer Disease. Archives of Internal Medicine, 163, 1524–1528.CrossRefGoogle ScholarPubMed
Haley, A.P., Gonzales, M.M., Tarumi, T., Miles, S.C., Goudarzi, K., & Tanaka, H. (2010). Elveated cerebral glutamate and myo-inositol levels in cognitively normal middle-aged adults with metabolic syndrome. Metabolic Brain Disease, 25, 397–405.CrossRefGoogle Scholar
Hayes, A.F. (2009). Beyond Baron and Kenny: Statistical mediation analysis in the new millenium. Communication Monographs, 76, 408–420.CrossRefGoogle Scholar
Kanaya, A., Lindquist, K., Harris, T.B., Launer, L., Rosano, C., Satterfield, S., & Yaffe, K. (2009). Total and regional adiposity and cognitive change in older adults. Archives of Neurology, 66, 329–335.CrossRefGoogle ScholarPubMed
Kannel, W.B., Cupples, L.A., Ramaswami, R., Stokes, J., Kreger, B.E., & Higgins, M. (1991). Regional obesity and risk of cardiovascular disease: The Framingham study. Journal of Clinical Epidemiology, 44, 183–190.CrossRefGoogle ScholarPubMed
Kaur, S., Gonzales, M.M., Strasser, B., Pasha, E., McNeely, J., Tanaka, H., & Haley, A.P. (2015). Central adiposity and cortical thickness in midlife. Psychosomatic Medicine, 77, 671–678.CrossRefGoogle ScholarPubMed
Kernie, S.G., Leibl, D., & Parada, L.F. (2000). BDNF regulates eating behavior and locomotor activity in mice. EMBO Journal, 19, 1290–1300.CrossRefGoogle ScholarPubMed
Kerwin, D.R., Gaussoin, S.A., Chlebowski, R.T., Kuller, L.H., Vitolins, M., Coker, L.H., … Women’s Health Initiative Memory Study. (2011). Interaction between body mass index and central adiposity and risk of incident cognitive impairment and dementia: Results from the Women’s Health Initiative Memory Study. Journal of the American Geriatric Society, 59(1), 107–112. doi:10.1111/j.1532-5415.2010.03219.x CrossRefGoogle ScholarPubMed
Khan, L.K., Sobush, K., Keener, D., Goodman, K., Lowry, A., Kakietek, J., … Centers for Disease Control and Prevention. (2009). Recommended community strategies and measurements to prevent obesity in the United States. MMWR Morbidity and Mortality Weekly Reports, 58, 1–26.Google ScholarPubMed
Kopelman, P. (2000). Obesity as a medical problem. Nature, 404, 635–643.CrossRefGoogle ScholarPubMed
Kordower, J., Palfi, S., Chen, E.-Y., & Shuang, Y. (2001). Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Annals of Neurology, 46, 419–424.3.0.CO;2-Q>CrossRefGoogle Scholar
Krystal, J.H., Karper, L., Seibyl, J.P., Freeman, G.K., Delaney, R., Bremner, J.D., & Charney, D.S. (1994). Subanesthetic efects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive and neuroendocrine responses. Archives of General Psychiatry, 51, 199–214.CrossRefGoogle Scholar
Lafosse, J.M., Reed, B., Mungas, D., Sterling, S.B., Wahbeh, H., & Jagust, W. (1997). Fluency and memory differences between ischemic ascular dementia and Alzheimer’s disease. Neuropsychology, 11, 514–522.CrossRefGoogle Scholar
Lang, U.E., Gunther, L., Scheuch, K., Klein, J., Eckhart, S., Hellweg, R., & Oehler, J. (2009). Higher BDNF concentrations in the hippocampus and cortex of an aggressive mouse strain. Behavioral Brain Research, 197, 246–249.CrossRefGoogle ScholarPubMed
Langbaum, J., Chen, K., Launer, L.J., Fleisher, A.S., Lee, W., Liu, X., & Reiman, E.M. (2012). Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons. Neurobiology of Aging, 33, 827.CrossRefGoogle ScholarPubMed
Leckie, R.L., Oberlin, L.E., Voss, M.W., Prakash, R.S., Szabo-Reed, A., … Erickson, K.I. (2014). BDNF mediates improvements in executive function following a 1-year exercise intervention. Frontiers in Human Neuroscience, 8, 985.CrossRefGoogle ScholarPubMed
Levinger, I., Goodman, C., Matthews, V., Hare, D.L., Jerums, G., Garnham, A., & Selig, S. (2008). BDNF, metabolic risk factors and resistance training in middle aged individuals. Medicine and Science in Sports and Exercise, 40, 535–541.CrossRefGoogle ScholarPubMed
Lezak, M., Howieson, D., Loring, D., Hannay, H., & Fischer, J.S. (2004). Neuropsychological assessment (4th ed.). New York: Oxford University Press.Google Scholar
Lokken, K.L., Boeka, A.G., Austin, H.M., Gunstad, J., & Harmon, C.M. (2009). Evidence of executive dysfunction in extremely obese adolescents. Surgery for Obesity and Related Diseases, 5, 547–552.CrossRefGoogle ScholarPubMed
Mandelman, S.D., & Grigorenko, E.L. (2012). BDNF Val66Met and cognition: All, none, or some? A meta-analysis of the genetic association. Genes, Brain and Behavior, 11, 127–136.CrossRefGoogle ScholarPubMed
Marques-Iturra, I., Garolera, M., Pueyo, R., Segura, B., Hernan, I., Garcia-Garcia, I., & Jurado, M.A. (2014). The interaction effect between BDNF val66met polymorphism and obesity on executive functions and frontal structure. American Journal Medical Genetics B Neuropsychiatry Genetics, 165B, 245–253.CrossRefGoogle Scholar
Mattson, M., Maudsley, S., & Martin, B. (2004). BDNF and 5-HT: A dynamic dua in age-related neuronal plasticity and neurodegenerative disorders. Trends in Neurosciences, 27, 581–594.CrossRefGoogle Scholar
Miyajima, F., Ollier, W., Mayes, A., Jackson, A., Thacker, N., Rabbitt, P., & Payton, A. (2008). Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes, Brain and Behavior, 7, 411–417.CrossRefGoogle ScholarPubMed
Murakami, S., Imbe, H., Morikawa, Y., Kubo, C., & Senba, E. (2005). Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly. Neuroscience Research, 53, 129–139.CrossRefGoogle ScholarPubMed
Nakagawa, T., Ono-Kishino, M., Sugaru, E., Yamanaka, M., Taiji, M., & Noguchi, H. (2002). Brain-Derived Neurotrophic Factor (BDNF) regulates glucose and energy metabolism in diabetic mice. Diabetes Metabolism Research Reviews, 18, 185–191.CrossRefGoogle ScholarPubMed
NCHS. (2006). The chartbook on trends in the health of Americans. Hyattsville, MD: NCHS.Google Scholar
Ochs, G., Penn, R., York, M., Giess, R., Beck, M., Tonn, H., & Toyka, K.V. (2000). A phase I/II study of recombinant brain-derived neurotrophic factor administrered by intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis, 1, 201–206.CrossRefGoogle ScholarPubMed
Ogden, C.L., Carroll, M.D., Kit, B.K., & Flegal, K.M. (2014). Prevalence of childhood and adult obesity in the United States, 2011-2012. Journal of the American Medical Association, 311, 806–814.CrossRefGoogle ScholarPubMed
Oliff, H.S., Berchstold, N.C., Isackson, P., & Cotman, C.W. (1998). Exercise-induced regulation of brain-derived neurotrophic factor (BDNF) transcripts in the rat hippocampus. Molecular Brain Research, 61, 147–153.CrossRefGoogle ScholarPubMed
Ozan, E., Okur, H., Eker, C., Gonul, A.S., & Akarsu, N. (2010). BDNF gene val66met polymorphism and gender on serum levels of BDNF. Brain Research Bulletin, 81, 61–65.CrossRefGoogle Scholar
Patterson, S.L., Abel, T., Deuel, T.A.S., Martin, K.C., Rose, J.C., & Kandel, E.R. (1996). Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron, 16, 1137–1145.CrossRefGoogle ScholarPubMed
Phillips, H.S., Hains, J.M., Armanini, M., Laramee, G.R., Johnson, S.A., & Winslow, J.W. (1991). BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron, 7, 695–702.CrossRefGoogle ScholarPubMed
Preacher, K.J., & Hayes, A. (2004). SPSS and SAS procedures for estimating indirect effects in simple mediation models. Behavior Research Methods, Instruments and Computers, 36, 717–736.CrossRefGoogle ScholarPubMed
Peng, Q., Masuda, N., Jiang, M., Li, Q., Zhao, M., Ross, C.A., & Suan, W. (2007). The antidepressant srtraline improves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington’s disease mouse models. Experimental Neurology, 210, 154–163.CrossRefGoogle Scholar
Raji, A., Seely, E.W., Arky, R.A., & Simonson, D.C. (2001). Body fat distribution and insulin resistance in healthy Asian Indians and Caucasians. Journal of Clinical Endocrinology and Metabolism, 86, 5366–5371.CrossRefGoogle ScholarPubMed
Rios, M., Fan, G., Fekete, C., Kelly, J., Bates, B., Kuehn, R., & Jaenisch, R. (2001). Conditional deletion of brain-derived neurotrophic factir in the postnatal brain leads to obesity and hyperactivity. Molecular Endocrinology, 15, 1748–1757.CrossRefGoogle ScholarPubMed
Ritchie, S.A., & Connell, J.M.C. (2007). The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Nutrition, Metabolism and Cardiovascular Diseases, 17, 319–326.CrossRefGoogle ScholarPubMed
Reitan, R. (1958). Validity of the Trail Making Test as an indicator of organic brain damage. Perceptual Motor Skills, 8, 271–276.CrossRefGoogle Scholar
Rossi, C., Angelucci, A., Constantin, L., Brashi, C., Mazzantini, M., Babbini, F., & Caleo, M. (2006). Brain-Derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. European Journal of Neuroscience, 24, 1850–1856.CrossRefGoogle ScholarPubMed
Ruff, R.M., Light, R., Parker, S.B., & Levin, H.S. (1996). Benton controlled oral word association test: Reliability and updated norms. Archives of Clinical Neuropsychology, 11, 329–338.CrossRefGoogle ScholarPubMed
Schlosser, R., Hutchinson, M., Joseffer, S., Rusinek, H., Saarimaki, A., Stevenson, J., & Brodie, J.D. (1998). Functional magnetic resonance imaging of human brain activity in a verbal fluency task. Journal of Neurology, Neurosurgery, and Psychiatry, 64, 492–498.CrossRefGoogle Scholar
Schwartz, D.H., Leonard, J., Perron, M., Richer, L., Syme, C., Veillette, S., & Paus, T. (2013). Visceral fat is associated with lower executive functioning among adolescents. International Journal of Obesity (Lond), 2013(37), 1336–1343.CrossRefGoogle Scholar
Sidak, Z. (1967). Rectangular confidence region for the means of multivariate normal distributions. Journal of the American Statistical Association, 62, 626–633.Google Scholar
Starkstein, S.E., Sabe, L., Vazquez, S., Teson, A., Petracca, G., Chemerinski, E., & Leiguarda, R. (1996). Neuropsychological, psychiatric and cerebral blood flow findings in vascular dementia and Alzheimer’s Disease. Stroke, 27, 408–414.CrossRefGoogle ScholarPubMed
Stingl, K., Kullman, S., Ketterer, C., Heni, M., Haring, H.-U., Fritsche, A., & Preissl, H. (2012). Neuronal correlates of reduced memory performance in overweight subjects. Neuroimage, 60, 362–369.CrossRefGoogle ScholarPubMed
Waldstein, S.R., Katzel, L.I. (2006). Interactive relations of central versus total obesity, blood pressure and cognitive function. International Journal of Obesity, 30, 201–207.CrossRefGoogle ScholarPubMed
Weschler, D. (1997). WAIS-III administration and scoring manual (3rd ed.). San Antonio: The Psychological Corporation.Google Scholar
Wolfe, N., Linn, R., Babikian, V.L., & Albert, M.L. (1990). Frontal systems impairments following multiple lacunar infarcts. Archives of Neurology, 47, 129–132.CrossRefGoogle ScholarPubMed
World Health Organization. (2008). Waist circumference and waist-hip ratio: Report of a WHO Expert Consulation. Geneva, Switzerland: WHO.Google Scholar
World Health Organization. (2009). Global health risks: Mortality and burden of disease attributable to selected major risks. Geneva, Switzerland: WHO.Google Scholar
Wrann, C.D., White, J.P., Salogiannis, J., Laznik-Bogoslavski, D., Wu, J., Ma, D., & Spiegelman, B.M. (2013). Exercise induces hippocampal BDNF through a PGC-1a/FNDC5 Pathway. Cell Metabolism, 18, 649–659.CrossRefGoogle Scholar
Wu, A., Ying, Z., & Gomez-Pinilla, F. (2004). The interplay between oxidative stress and brain-derived neruotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cogntion. European Journal of Neuroscience, 19, 1699–1707.CrossRefGoogle Scholar